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SECOND MESSANGERS

SECOND MESSANGERS. DR AMINA TARIQ BIOCHEMISTRY. Basic Characteristics Of Cell Signaling . Cell must respond appropriately to external stimuli to survive. Cells respond to stimuli via cell signaling. Each cell is programmed to respond to specific combinations of extracellular signal molecules.

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SECOND MESSANGERS

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  1. SECOND MESSANGERS DR AMINA TARIQ BIOCHEMISTRY

  2. Basic Characteristics Of Cell Signaling • Cell must respond appropriately to external stimuli to survive. • Cells respond to stimuli via cell signaling

  3. Each cell is programmed to respond to specific combinations of extracellular signal molecules

  4. Different cells can respond differently to the same extracellular signal molecule

  5. Signal Molecules and Receptors

  6. Some small hydrophobic hormones (steroid hormones) whose receptors are intracellular gene regulatory proteins

  7. Amino Acid Hormones • Amino acids cannot cross the cell membrane. • Amino acid hormones bind with a protein on the outside of the cell membrane A) General Steps: 1. Hormone Receptor 2. Effectors Enzyme 3. Second Messenger 4. Metabolic Responses Triggered

  8. G Protein–Coupled Receptors (GPCR) • These receptors typically have seven hydrophobic plasma membrane-spanning domains. • Many of the group II hormones bind to receptors that couple to effectors through a GTP-binding protein intermediary.

  9. AdenylylCyclase • Different peptide hormones can either stimulate (s) or inhibit (i) the production of cAMP from adenylylcyclase

  10. Two parallel systems, a stimulatory (s) one and an inhibitory (i) one, converge upon a catalytic molecule (C). • Each consists of a receptor, Rs or Ri, and a regulatory complex, Gs and Gi

  11. Gs and Giare each trimers composed of α, β and γ subunits. • Because the αsubunit in Gs differs from that in Gi the proteins, which are distinct gene products, are designated s and i

  12. Hormones That Stimulate AdenylylCyclase (Hs • ACTH • ADH • β2-Adrenergics • Calcitonin • CRH • FSH • Glucagon • hCG • LH • MSH • PTH • TSH

  13. Hormones That Inhibit AdenylylCyclase (HI) • Acetylcholine • α2-Adrenergics • Angiotensin II • Somatostatin

  14. The αs protein has intrinsic GTPase activity. • The active form, αs·GTP, is inactivated upon hydrolysis of the GTP to GDP • the trimeric Gs complex (αβγ) is then re-formed and is ready for another cycle of activation.

  15. Cholera and pertussis toxins catalyze the ADPribosylation of αs and αi-2 respectively. • In the case of αs, this modification disrupts the intrinsic GTPase activity; thus, αs cannot reassociate with and is therefore irreversibly activated.

  16. ADP ribosylation of αi-2 prevents the dissociation of αi-2 from βγ , and free αi-2 thus cannot be formed. • αs activity in such cells is therefore unopposed.

  17. Second Messenger: Cyclic-AMP (cAMP) 1. Hormone Receptor (first messenger) • Hormone binds to the plasma membrane at a specific site. • Receptor protein changes shape and activates the G protein.

  18. 2. Effector Enzyme • G protein complex activates adenylatecyclase.  • Adenylatecyclase breaks GTP to GDP.  • Generates second messengercyclic-AMP from ATP.

  19. Second Messenger • cyclic-AMP moves around the cell triggering chemical reactions with protein kinases.

  20. The second messenger is a kinase or phosphatase cascade: • Chorionic somatomammotropin • Epidermal growth factor • Erythropoietin • Fibroblast growth factor • Growth hormone • Insulin • Insulin-like growth factors I and II • Nerve growth factor • Platelet-derived growth factor • Prolactin

  21. Protein Kinase • cAMP binds to a protein kinase called protein kinase A (PKA) • It is a heterotrimeric molecule- 2 regulatory and 2 catalytic subunits. • cAMP binds to the regulatory subunit and catalytic is free and activated.

  22. This catalytic subunit catalyzes the transfer of phosphate of ATP to other proteins, i.e. causes phosphorylation.

  23. Phosphoproteins • There are certain substrates for phosphorylation which defines a target tissue and the extent of a particular response within a given cell. • Control the effects of cAMP

  24. The control of any of the effects of cAMP, including such diverse processes as steroidogenesis, secretion, ion transport, carbohydrate and fat metabolism, enzyme induction, gene regulation, synaptic transmission, and cell growth and replication, could be conferred by a specific protein kinase, by a specific phosphatase, or by specific substrates for phosphorylation.

  25. CREB (cAMP response element binding protein)binds to CRE.

  26. CREB binds to a cAMP responsive element (CRE) in its nonphosphorylated state and is a weak activator of transcription. • When phosphorylated by PKA, CREB binds the coactivatorCREB-binding protein CBP/p300 and as a result is a much more potent transcription activator.

  27. Phosphodiestrases • They terminate the action of cAMP by its hydrolysis to 5´-AMP. • Thus they increase the intracellular signals and prolong the action of hormones through this signal.

  28. These are subject to regulation by their substrates, cAMP and cGMP; by hormones; and by intracellular messengers such as calcium, probably acting through calmodulin. • Most significant inhibitors of phosphodiestrase are methylatedxanthine derivatives such as caffeine

  29. Phosphatases • They are responsible for protein dephosphorylation.

  30. The second messenger is cGMP • Atrialnatriuretic factor • Nitric oxide

  31. NO – guanylcyclase (soluble form) – GTP –cGMP – PKG- muscle relaxation

  32. Atrialnatriuretic peptide -guanylcyclase (membrane bound form) – GTP –cGMP – PKG- natriuresis, diuresis, vasodilatation, inhibition of aldosterone secretion

  33. Increased cGMP activates cGMP dependent protein kinase- protein kinase G which in turn phosphorylate the proteins • Muscle relaxation and dilatation of blood vessels • Nitroprusside, Nitroglycerin, Nitric oxide, sodium azide all are vasodilators.

  34. Second Messenger is Calcium or PI • Acetylcholine • Angiotensin II • Antidiuretic hormone • Cholecystokinin • Gastrin • Gonadotrophin releasing hormone • Oxytocin • PDGF • TRH

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